As disclosed in European Patent Application No. 0107930 (Cale et al.), it is known that aromatic 2-aminoalkyl-2,3-dihydro-1,4-oxazepin-5(4H)-ones and sulfur analogs thereof are compounds which are useful as antihistamines and which can be prepared, e.g., by (1) reacting a precursor acid with a precursor alcohol in the presence of a sodium compound, (2) halogenating and fusing the resultant alkali metal salt, (3) optionally thiating the aromatic 2-haloalkyl-2,3-dihydro-1,4-oxazepin-5(4H)-one or 1,4-thiazepin-5(4H)-one thus prepared, (4) aminating the ketone product of step 2 or the thione product of step 3, and (5) when desired, quaternizing the resultant amine or reacting it with a suitable acid to form a pharmaceutically-acceptable salt. This process, like the other processes taught by Cale et al. for the preparation of their pharmaceuticals, is effective but has the disadvantages of requiring multiple isolations of intermediates and typically providing the product in low yield.
An important factor leading to this low yield appears to be the inefficiency of the halogenation/fusion operation. The relevant working examples of Cale et al., i.e., Intermediates 1-9, show that their various halogenation/fusion reactions result in yields of only 23-60%, based on the starting materials for those reactions, and only about 1-27%, based on the amount of precursor acid or equivalent employed in the previous step. The patentees teach that other halogenating agents, such as phosphorus pentahalides, phosphorus trihalides, and triphenylphosphine dihalides, can be used in their reaction, but their teachings also indicate that other halogenating agents would be inferior to their preferred thionyl halides and combinations of triphenylphosphine with a carbon tetrahalide.
March, Advanced Organic Chemistry, Second Edition, McGraw-Hill, New York, page 633, teaches that oxalyl chloride has been used as a halogenating agent.